Compositions and methods

ABSTRACT

An ascorbic acid-based composition and related method for the treatment of aging, photo-damaged or inflamed skin is disclosed. The composition includes water and ascorbic acid, at least a portion of which has generally been pretreated by being dissolved under relatively high temperature and concentration conditions. The composition typically includes at least about 5.0% (w/v) ascorbic acid formulated to have a pH above 3.5. 10 to 50% of the ascorbic acid is pretreated ascorbic acid. The composition may also include a non-toxic zinc salt, a tyrosine compound, and/or pharmaceutically acceptable carrier. The composition may include an anti-inflammatory compound, such as aminosugar and/or sulfur-containing anti-inflammatory compound. Embodiments containing an aminosugar such as glucosamine are further useful for treating rosacea and other inflammatory skin ailments. The composition may be administered in a variety of forms suitable for topical application on skin.

[0001] This application is a continuation-in-part of, and claimspriority from co-pending U.S. patent application Ser. No.: 09/732,385,filed Dec. 7, 2000, which is a continuation of application Ser. No.09/356,142, filed Jul. 19, 1999, which claims benefit of ProvisionalApplication Ser. No. 60/125,356, filed Mar. 19, 1999.

BACKGROUND OF THE ART

[0002] Skin is composed of a top layer, the epidermis, which isapproximately 20 cell layers or about 0.1 mm in thickness, and a lowerlayer, the dermis, which is from about 1 to about 4 mm in thickness andcontains small blood vessels, collagen, elastin and fibroblasts. Thedermis provides structural support and nutrients to the epidermis. Aginghas been shown to increase cellular heterogeneity of the epidermallayer, however, it has little effect on the thickness of the epidermallayer. The supporting dermis, on the other hand, is known to thin withage and exposure to the sun and environmental contaminants. The dermallayer provides the support and blood supply for the epidermis, thereforethe dermal layer is important in maintaining the elasticity andappearance of the skin. Disruption of the supporting dermis leadsdirectly to sagging and consequent furrowing of the epidermis, i.e., theformation of wrinkles.

[0003] Deep wrinkles are also due to continual stretching andcontraction of both the dermis and epidermis. Currently, these deepwrinkles or furrows may only be eliminated by plastic surgery or bycollagen injections directly beneath the depressed areas. The finewrinkles that occur with age and prolonged exposure to the sun and otherenvironmental contaminants are the direct result of deterioration of thesupporting dermal layer. Other environmental effects on the skin arediscussed in U.S. Pat. Nos. 4,938,969 and 5,140,043.

[0004] As a result of the aging process and damage caused by incidentradiation, a disruption of the collagen bundles that provide support tothe epidermis is observed. Collagen exists normally in dense, organizedpatterns. During the aging process collagen becomes disorganized andless supportive of the epidermis and the dermis loses elasticity. Thereis also progressive loss of circulatory support from the small bloodvessels that are more numerous and close to the surface in young skin.The result of aging on skin, whether or not it has been accelerated byincident radiation, is a deterioration of the dermal layer—fewerfibroblasts, less collagen, less elastin and less circulatory support.Consequently, the normal stretching and contraction of the skin leads todamage of the dermis that is not readily corrected and wrinklingresults.

[0005] Dermatologists and cosmetologists have directed their efforts toimproving the appearance of skin using agents known to stimulate thegrowth and proliferation of epidermal cells. Newly proliferated cellsprovide more structure and hold more moisture, giving the skin a youngerappearance. One method of causing new skin cell proliferation isaccomplished by use of an irritant or chemical peel in which theuppermost layers of the epidermis are caused to slough off, leading toproliferation and replacement with new epidermal cells. While suchtreatment is recognized to provide some cosmetic improvement, it doesnot address the major causative factor, namely, the compromisedsupporting dermal layer.

[0006] Considerable effort has also been expended to find ways toprevent adverse changes in the skin brought about by ultraviolet (UV)exposure. Preventative approaches include physically blocking orabsorbing the UV radiation before it can enter the skin using UVabsorbing compounds. Blocking and absorbing are effective but arecumbersome because sun blockers or absorbers must be applied beforeevery exposure and may be washed off with water. For example, afterswimming UV absorbing compounds must typically be reapplied. Further,the long-term side effects of many of the compositions containing sunblockers and/or absorbers are not known.

[0007] L-ascorbic acid has many known biological functions fromenzymatic cofactor to “sparing” agent against vitamin E depletion. See,for example, Englard and Seifter, “The Biochemical Functions of AscorbicAcid,” Ann. Rev. Nutri. 6:365-406, (1986); Kunert and Tappel, “TheEffect of Vitamin C on in vivo Lipid Peroxidation in Guinea Pigs asMeasured by Pentane and Ethane Production, Lipids 18:271-74 (1983). Thelatter function of L-ascorbic acid may partly account for its“anti-oxidant” status. Additionally, at higher concentrations, ascorbicacid is known to react with both the super oxide and hydroxyl radicals.The super oxide, and the hydrogen peroxide and hydroxyl radicalsubsequently generated, are oxygen-containing free radicals now known tobe generated in vivo under a variety of normal and pathologicalconditions. These radicals have been implicated as causative agents foreverything from sunburn to aging and are believed to destroy lipidmembranes, break down DNA and inactivate enzymes, among other effects.An immense amount of work has been done in the last two decadesdocumenting the deleterious behavior of oxygen radicals. Several recenttexts on the subject include: Oxy-radicals in Molecular Biology &Pathology, D Cerutti, 1. Fridovich, J. McCord, eds., (Alan R. Liss, Inc.New York, 1988); Biological Role of Reactive Oxygen Species in Skin, 0.Hayaishi, S. Inamura, Y. Mayachi, eds. (Elsevier Press, New York, 1987);Free Radicals, Aging and Degenerative Diseases, J. E. Johnson, Jr., R.Walford, D. Harmon, J. Miguel, eds. (Alan Liss, Inc., New York, 1986);Free Radicals in Biology and Medicine, B. Halliwell and J. M. C.Gutteridge, eds., (Clarendon Press, Oxford, 1985); and Oxidative StressHelmut Sies, ed. (Academic Press, 1985). Also addressing the subject areseveral symposia, including “Oxygen Radicals and Tissue Injury”Proceedings from an Upjohn Symposium (April, 1987); and “Oxygen FreeRadicals,” Proceedings from National Heart, Lung & Blood Institute(National Institute of Health, Washington, D.C., December 1987).

[0008] As a result of the known effects of the use of ascorbic acid ondamaged and aging skin, there are now various Vitamin C or ascorbic acidointments, serums and creams that are used with varying degrees ofsuccess to prevent and/or repair damage to the skin's dermal layer. Forexample, it has been reported that a composition including ascorbicacid, tyrosine and a non-toxic zinc salt, preferably zinc sulfate, in avehicle suitable for topical application, when applied to areas showingthe fine wrinkles associated with aging/sun exposure, results in areadily perceivable diminution of the fine wrinkle structure. It hasalso been reported that ascorbic acid topical aqueous compositions areunstable unless maintained at a pH below about 3.5. Topical compositionscontaining a carrier and a concentration of L-ascorbic acid above about1% (w/v) may be stable if maintained at a pH below about 3.5 or evenbelow about 2.5.

[0009] In addition to ameliorating skin damaged by age or environmentalinsult, topical ascorbic acid formulations may also exhibit someeffectiveness in the treatment of various inflammatory skin maladiessuch as, for example, inflammatory rosacea, allergic inflammations andhypersensitivity. A few cases in which a topical formulation of ascorbicacid, zinc and tyrosine was applied to rosacea, for example, a slightimprovement was observed with long-term use. Such formulations, however,have not been shown to clear up rosacea to a substantial extent and evenslight improvement requires long-term, diligent daily application to theaffected skin. Improved formulations of topical ascorbic acid are neededto effectively and quickly treat skin maladies such rosacea, allergicinflammations and hypersensitivity.

[0010] Currently available ascorbic acid compositions and methods failto provide the delivery system for formulations having the desiredcombination of efficacy, non-irritability, stability and convenientstorage solutions for topical Vitamin C applications. A significantproblem of current compositions is that it is not practical to use morethan 15% (w/v) ascorbic acid in a serum, cream gel or other suitabletopical formulation for cosmetic use because the low inherent pH (circa2-2.5) of such a formulation is often quite irritating to the skin. Thebreakdown of the ascorbic acid in such low pH formulations due toexposure to water, heat, and air can also lead to undesirablediscoloration and eventually loss of efficacy. Furthermore, if theascorbic acid is formulated in a cream with limited water content toenhance stability of the ascorbic acid over time, changes in heat,atmospheric pressure and/or moisture content may activate the ascorbicacid, leading to unacceptable expansion and even explosion of thecontainers holding such creams or gels. There is, therefore, acontinuing need for topical ascorbic acid-based compositions thatimprove the efficacy and stability of such skin treatment formulations.

SUMMARY OF THE INVENTION

[0011] The present invention provides stable, effective topicalcompositions that include ascorbic acid, generally in a relatively highpH formulation. The concentration of active ascorbic acid that isavailable to be delivered to the skin is maintained at a highconcentration, while at the same time lowering the irritating effectscommonly associated with aqueous compositions having a highconcentration of organic acid. By providing, for example, a portion ofthe total ascorbic acid of the composition in the ascorbate salt form,the composition disclosed herein decreases the overall irritant natureof the solution without losing efficacy or desired biological effect.The present ascorbic acid-based composition are particularly effectivefor topical application to reduce epidermal wrinkling, such as thatresulting from intrinsic aging or photo damage. For example, applyingthe present compositions within about six hours to skin that hasreceived excess sun damage can attenuate the effects due to UV exposureand decrease sunburn and cell damage. In addition, the compositionsdisclosed herein did not expand or lose integrity on storage. Thepresent compositions were also far less likely to oxidize to yield anoff color (e.g., to become darker or brown). Subjects using the presentascorbic acid formulations found the product to be very effective, andto yield rapid results relative to decreasing the appearance of finelines.

[0012] In addition to treating aged or damaged skin, the presentinvention further includes compositions and methods for treatinginflammatory skin ailments such as inflammatory rosacea. The presentinvention provides formulations of ascorbic acid in combination with ananti-inflammatory agent such as, for example, glucosamine or othersuitable aminosugar. Such combination formulations demonstratesignificant improvement in the treatment of inflammatory ailments of theskin such as, for example, rosacea, in comparison to formulations ofascorbic acid without, for example, glucosamine. Formulations of thepresent invention that include glucosamine are particularly useful overprior art formulations for treating inflammatory ailments of the skinthat have demonstrated resistance to prior art treatments.

[0013] Conventional treatment for rosacea is cortisone therapy.Long-term use of cortisone is undesirable, however, because it weakensthe strength and resilience of connective tissue. Another drawback ofcortisone use is the rebound effect that occurs when the use ofcortisone is temporarily discontinued. The present invention provides atreatment for rosacea that does not have the undesirable effects ofcortisone and that is effective for individuals that are resistant tocortisone treatment. Methods are provided to combine glucosamine, forexample, with ascorbic acid so that the ingredients maintain efficacyand achieve a stable shelf life in formulations suitable for topicalapplication to the skin.

[0014] The present compositions typically include up to about 50% of thetotal ascorbic acid present that has been prepared by dissolution inwater at relatively high temperature and concentration. Ascorbic aciddissolved in this manner is referred to herein as “pretreated” ascorbicacid and is prepared by dissolving a high concentration of ascorbicacid, typically at least about 20% (w/v) (i.e., at least about 200mg/ml) in water at 60° to 90° C.

[0015] Importantly, compositions of a cream, or other suitableadministration form of the present invention, containing 50% (w/v)ascorbic acid content in the form of pretreated ascorbic acid,formulated as described herein, are stable. That is, such compositionsdo not expand, explode, or discolor due to heat, changes in atmosphericpressure, or improper storage, all of which have proved to be problemsin manufacturing, storing and distributing formulations of pureL-ascorbic acid and its direct break down products. Further,compositions of the present invention that comprise a combination ofpretreated ascorbic acid and glucosamine are also stable.

[0016] Embodiments of the present compositions commonly include water,at least about 5.0% (w/v) ascorbic acid, and have a pH of more than 3.5.The compositions typically also include (a) non-toxic zinc salt and/or(b) a stimulant of protein synthesis and/or precursor to melaninsynthesis (e.g., a tyrosine compound). The compositions may also includean anti-inflammatory compound, such as an aminosugar and/or asulfur-containing anti-inflammatory compound. The topical compositionsmay be in any of a number of common forms, such as an aqueous solution(“a serum”), a hydrophilic lotion-, an ointment-, a cream or a gel.Typically, the topical composition includes a pharmaceuticallyacceptable carrier and may also include one or more other formulationadditives, such as surfactant(s), thickener(s), dyes, other antioxidantsand/or fragrance.

[0017] The “high pH” formulations of the present compositions are lessirritating than high concentrations of L-ascorbic acid (with itsinherent low pH, e.g., circa 2.0-2.5) because the relatively higher pHavoids the skin irritation problem often encountered with harsh chemicalpeels or solutions with pH values below 3.5. The present compositionswere also found to be very stable on short and long term storage, whilemaintaining a high degree of effectiveness.

[0018] The present invention also includes a method of treating damageto skin, such as often arises due ultraviolet light exposure and/oraging, as well as treating rosacea or other inflammatory skinafflictions. The method includes applying the present topicalcomposition to a damaged or afflicted portion of the skin. For example,the present composition is typically applied topically to the locus ofwrinkles or the locus of rosacea.

BRIEF DESCRIPTION OF THE FIGURES

[0019] The invention will become more fully understood from thefollowing detailed description, taken in conjunction with theaccompanying drawings, in which:

[0020]FIG. 1 shows a C¹³ NMR of a 10% (w/v) solution of “native”ascorbic acid after storage for one week at 37° C.

[0021]FIG. 2 shows a C¹³ NMR of a 1:1 mixture of a 10% (w/v) solution of“native” ascorbic acid and a 30% (w/v) solution of pretreated ascorbicacid after storage of the mixture (at pH 2.3) for one month at roomtemperature.

[0022]FIG. 3 shows a C¹³ NMR of a 30% (w/v) solution of pretreatedascorbic acid after storage for one week at 37° C.

[0023]FIG. 4 is a graphic rendering of before (A) and after (B)photographs of a subject who used an embodiment of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

[0024] While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatmay be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

[0025] Long shelf-life and extended stability (e.g., for at least twoyears) is normally required for any cosmetic product to be distributedthrough ordinary channels in which there must be stored inventory tomeet market demand without the concern that the inventory willdeteriorate before being sold. The present ascorbic acid-basedcompositions have good efficacy and storage stability, and low skinirritability. These topical ascorbic acid based compositions areparticularly effective for reducing epidermal wrinkling resulting fromintrinsic aging or photo damage. The compositions of the presentinvention may also be used prophylactically to ameliorate thephoto-induced damage that results from exposure of skin to sunlight andother harmful irradiation. Additionally, embodiments of the presentinvention in which ascorbic acid and glucosamine are combined are usefulfor treating skin afflicted with rosacea or other inflammatory skinconditions.

[0026] The compositions typically include at least about 5.0% (w/v)ascorbic acid. Herein, the amount of ascorbic acid present in acomposition refers to the total amount of ascorbic acid and ascorbatepresent stated as if all was present in the acid form. In other words, asolution which includes 0.5 mole ascorbic acid and 0.5 mole of anascorbate salt contains the same total amount of ascorbic acid as asolutions which include either 1.0 mole ascorbic acid or 1.0 mole of anascorbate salt.

[0027] The present compositions commonly include at least about 5.0%(w/v) total ascorbic acid, which may comprise ascorbic acid in the formof monohydroascorbic acid or ascorbate salts. It is generallyadvantageous to include higher concentrations of ascorbic acid,typically at least about 10% (w/v) and often concentrations in the rangeof about 15 to about 25% (w/v) ascorbic acid. Because of the potentialproblems of skin irritation with formulations containing highconcentrations of ascorbic acid, it is generally advantageous to adjustthe pH of such formulations to at least about 3.5. To achieve an optimumcombination of low irritability and high stability, the presentcompositions are typically formulated to have a pH of about 3.7 to about4.1 and, for example, between about 3.8 to about 4.0. Compositions ofthe present invention may further include anti-inflammatory agents suchas glucosamine in combination with ascorbic acid.

[0028] It has been found that ascorbic acid-based topical formulationsin which a substantial portion of the ascorbic acid has been pretreatedin accordance with the present invention exhibit particularly goodstorage stability. As noted above, for the purposes of this application,“pretreated” ascorbic acid also refers to ascorbic acid that has beendissolved in water at a relatively high temperature to form aconcentrated ascorbic acid solution. Typically, the ascorbic acid isdissolved in water at between about 60 to about 90° C. (e.g., betweenabout 75 to about 80° C.) to form a concentrated solution that containsat least about 20% (w/v) ascorbic acid. The ascorbic acid is dissolvedin the acid form, i.e., the resulting solution will have a relativelylow pH (circa 2.0-2.5). After dissolution, the concentrate is generallyheated for an additional period of time (e.g., 0.25 to 1.0 hour) andcooled to below about 40° C. before being incorporated into the finalformulation. If the pretreated ascorbic acid concentrate is to be storedprior to formulation, it may be stored at room temperature or below(e.g., about 3 to about 20° C.) and/or under conditions that excludeoxygen-containing gases such as air (e.g., in a sealed container orblanketed with an inert gas such as argon or nitrogen). In the presentcompositions, at least about 10% of the ascorbic acid present may bepretreated ascorbic acid. Typically, no more than about 50% of theascorbic acid present has been pretreated to obtain the enhancedstability properties of the compositions while minimizing the additionalprocessing steps and costs associated with the pretreatment of theascorbic acid.

[0029] To test and quantitate the stability of composition containingpretreated ascorbic acid, nuclear magnetic resonance (NMR) spectra ofstored samples of the following ascorbic acid-based solutions: (i) a 10%(w/v) solution of “native” ascorbic acid; (ii) a 1:1 mixture of the 10%(w/v) solution of “native” ascorbic acid and a 30% (w/v) solution ofpretreated ascorbic acid; and (ii) the 30% (w/v) solution of pretreatedascorbic acid after storage. The results, shown in FIGS. 1, 2 and 3respectively, demonstrate the stability of the solutions under storageconditions. Somewhat accelerated storage testing is often carried out bystoring solutions at 37° C. The results of tests (see, e.g., FIGS. 1 and3) demonstrated that both a 10% (w/v) solution of “native” ascorbic acidand a 30% (w/v) solution of pretreated ascorbic acid were stable afterstorage at 37° C. for one week.

[0030] As an example, containers having a 1 to 20% (w/v) concentrationof a mixture of pretreated ascorbic acid in a 1:1 to 1:10 ratio,together with ascorbic acid formulated under more standard conditions(i.e., dissolved or added in solid form to a formulation at temperaturesof about 20 to about 40° C.—“native ascorbic acid”) were quite stablewhen shipped and/or stored under adverse conditions, or even whenheated. The stability of such formulations was enhanced in comparison toconventional low pH formulations containing untreated ascorbic acid,e.g., low pH creams containing 10% (w/v) untreated ascorbic acid. It ispostulated that the observed stability of the present compositions isafforded by an equilibrium reaction between ascorbic acid andmonhydroascorbic acid that maintains a stable solution of ascorbic acid.

[0031] The present compositions generally also include a non-toxic zincsalt. The zinc salt may be a water-soluble zinc salt such as zincsulfate. The zinc salt is generally present in about 0.5 to about 5.0%(w/v). Very effective results can typically be obtained withcompositions that include no more than about 3.0% (w/v) zinc salt. Forexample, a number of present compositions are commonly formulated withabout 0.5 to about 2.0% (w/v) zinc sulfate together with the othercomponents described herein.

[0032] The composition of the present invention may further include oneor more compounds capable of serving as a stimulant of protein synthesisand/or precursor to melanin synthesis. This component is generallypresent in about 1 to about 10% (w/v), and, for example, between about 3to about 8% (w/v), based on the total composition. Typically, thiscomponent includes a tyrosine compound. As employed herein, a “tyrosinecompound” is tyrosine or a compound that is capable of generatingtyrosine upon chemical and/or biological transformation. Examples ofsuitable tyrosine compounds for use in the present compositions includetyrosine, N-acetyltyrosine, tyrosine ethyl ester hydrochloride, andtyrosine phosphate.

[0033] The present compositions may also include a compound which canfunction as an anti-inflammatory agent. Examples of suitableanti-inflammatory agents include anti-inflammatory sulfur-containingcompounds and anti-inflammatory aminosugars. The sulfur-containinganti-inflammatory compound is typically a sulfur containing amino acidor related derivative such as cystine, cysteine, N-acetyl cysteine,glutathione, cysteamine, S-methylcysteine, methionine and the like.Examples of suitable anti-inflammatory aminosugars include glucosamine,mannosamine, N-acetylmannosamine, galactosamine,glucosamine-6-phosphate, Nacetylglucosamine, N-acetylmannosamine,N-acetylgalactosamine and the like. For example, by adding D-glucosaminehydrochloride to the present compositions (in circa 5-20% (w/v)),cellular damage due to excess sun exposure can be minimized even ifapplied roughly 12 hours after exposure due to the anti-inflammatoryeffects of glucosamine in concert with ascorbic acid.

[0034] In addition to treating aged or damaged skin, the presentinvention further includes compositions and methods for treatinginflammatory skin ailments such as rosacea, adult acne and likeinflammations. Conventional treatment for rosacea includes cortisonetherapy that involves continual use of cortisone, which causesconnective tissue thinning. Conventional treatment for non-inflammatoryrosacea (for example, red face due to surface blood vessels that becomeeven more prominent after exposure to the sun or to the cold) includesmetronizole, which is postulated to be an anti-inflammatory agent.Metronizole therapy requires continual use of metronizole whiletreatment is desired or necessary. Subjects that use cortisone ormetronizole, which both require continual use, typically suffer reboundor recurrence of their inflammation after discontinuing use of eitheragent. The present invention provides a treatment for inflammatoryrosacea that does not have the undesirable effects of cortisone and thatis effective for individuals that are resistant to cortisone treatment.The present invention provides the further benefit of decreasing oreliminating rebound of rosacea after discontinuance of use.

[0035] A composition of the present invention comprising, for example,approximately 14% ascorbic acid, 3.5% tyrosine, 1.5% zinc sulfate and20% glucosamine in a topical cream, ointment or lotion is effective forthe treatment of rosacea that is resistant to prior art treatments. Anembodiment of the present invention for the treatment of inflammatoryskin ailments such as rosacea includes a composition comprising ascorbicacid in the range of approximately 5% to 20% w/w in a pH range ofapproximately 3.7 to 4.1 and glucosamine in the range of approximately10% to 25%. Additional embodiments may further comprise zinc sulfateand/or tyrosine.

[0036] A feature of the present invention is the combination of ascorbicacid and glucosamine. These two substances do not ordinarily combinewell because the respective pHs are incompatible with each other. Mixingascorbic acid with glucosamine produces a soured, brown mush unless atleast a portion of the ascorbic acid is pretreated. For the combinationof the present invention to mix stably, the use of pretreated ascorbicacid, as described above, adjusted to a pH in the range of approximately3.8 to 4.0, produces a stable mixture of ascorbic acid and glucosamine.As described above, the pretreated ascorbic acid may be present in therange of approximately 10% to 50% of the total ascorbic acid in theformulation.

[0037] An embodiment of the present invention was used to treat a49-year-old woman of Greek descent who had severe rosacea on her facefor ten years and had used hydrocortisone constantly during this periodto partially control the inflammation. Topical use of the presentinvention by the subject on the area of inflammation for a week resultedin complete remission of the rosacea.

[0038] A second subject was a 34-year-old woman who suffered fromdisfiguring rosacea on her face for 14 years. The second subject usedhydrocortisone to partially control the inflammation, but even so sherarely went out in public and then only with heavy make-up. Afterfailure of the cortisone treatment to provide adequate relief, thesubject used an ascorbic acid, zinc sulfate and tyrosine formulationonce a day. The ascorbic acid composition provided slight relief, butthe subject's rosacea never cleared up adequately. The subject then usedthe same ascorbic acid formulation to which 20% (w/v) glucosamine hadbeen added. After one week of using an ascorbic acid/glucosaminecomposition of the present invention, her complexion showed markedimprovement. After three weeks of use, substantially all her blemishesdisappeared and she no longer has to wear make-up.

[0039]FIG. 4 provides an exemplary depiction of the cosmetic andtherapeutic benefits of the present invention. A subject used anembodiment of the present invention containing glucosamine for one week.Before using the embodiment (panel A), the subject suffered fromdisfiguring rosacea blemishes on her face. After one week of use (panelB), the subject shows marked improvement. In one week, the size ofblemishes has decreased and the intensity of the rosacea has abated,although some scarring (resulting from years of severe inflammatorylesions that had not responded to previous treatments) remains.

[0040] The ascorbic acid and tyrosine compound components of the presentcompositions may be formulated in part or whole in a neutralized or saltform. Acceptable amine salts include the acid addition salts (e.g.,formed with a free amino group of a tyrosine compound) and may be formedwith inorganic acids such as, for example, hydrochloric or phosphoricacids, or such organic acids as acetic, oxalic, tartaric, mandelic, andthe like. Salts formed with the free carboxyl groups may also be derivedfrom inorganic bases such as, for example, sodium, potassium, ammonium,calcium, or ferric hydroxides, and such organic bases as isopropylamine,trimethylamine, histidine, procaine and the like. As noted elsewhereherein, since the present compositions have a pH of about 3.5 or above(and typically at least about 3.7) the ascorbic acid is typically atleast partially present in the form of ascorbate salt(s), or possibly asan equilibrium reaction between ascorbic acid and monohydroascorbicacid. Commonly, the pH of the composition is adjusted to the desiredvalue by adding sufficient base, such as sodium hydroxide, potassiumhydroxide and/or ammonium hydroxide, to achieve the desired value. Insuch situations, the ascorbate would exist at least in part in the formof sodium hydroxide, potassium and/or ammonium ascorbate.

[0041] The water used for preparing the compositions of the presentinvention may be distilled and/or deionized, but any water may be usedthat does not contain contaminants that would affect the stability ofthe ascorbic acid present in the composition. For example, the presenceof certain metal ions such as copper and iron salts, is known to affectthe stability of ascorbic acid. The effects of water of varying purityon ascorbic acid stability is discussed in Meucci, et al., “AscorbicAcid Stability in Aqueous Solutions,” Acta Vitaminol. Enzymol. 7(34):147-54 (1985), the disclosure of which is incorporated herein byreference.

[0042] The present compositions typically also include apharmaceutically acceptable carrier. Carriers for topical applicationuseful in practicing the invention include, but are not limited to,alkyleneglycols, or alkyleneglycols in combination with one or morederivatives of hydroxyalkylcellulose. In one illustrative embodiment,the alkylene glycol is propyleneglycol and the hydroxyalkylcellulose ishydroxypropylcellulose. When a combination of alkyleneglycol andhydroxyalkylcellulose is used, a useful ratio of alkyleneglycol tohydroxyalkylcellulose is from about 30:1 to 5:1.

[0043] Without limitation, other carriers known to those skilled in theart that are compatible with water and are biologically orpharmaceutically acceptable are expected to provide equivalentcompositions within the scope of this invention. For example, alcoholssuch as ethanol and propanol, glycols such as butylene or hexyleneglycol, and polyols such as sorbitol or glycerol may be suitablyemployed. Other examples of suitable carriers include polyethylene orpolypropylene glycols. Also contemplated as carriers for use in thepresent compositions are biologically acceptable hydroxyalkylcelluloses.

[0044] The phrase “pharmaceutically acceptable” refers to molecularentities and compositions that do not produce an allergic or similaruntoward reaction when administered to a human. The pharmaceuticallyacceptable carriers and additives employed in the present compositionsare compatible with at least one formulation of the ascorbicacid/ascorbate mixture, tyrosine compound and zinc salt-containingcompositions as described herein.

[0045] Amino acids employed in the present compositions will generallybe in the left-handed chiral form of the amino acid (i.e., L-aminoacid(s)). The amino acids should be as pyrogen free as possible andshould meet sterility, pyrogenicity, general safety and purity standardsas required by FDA Office of Drug standards. The amino acids may evenact as buffers for the present solutions or may even be used to adjustthe pH of the solution to above 3.5.

[0046] Illustrative examples of the present compositions can be producedas follows. The appropriate amounts of the acid forms of native anduntreated ascorbic acid are mixed and/or dissolved in water. A watersoluble, non-toxic zinc salt is then added and the mixture is mixed (viastirring or agitation) until the zinc salt has dissolved. Othercomponents, such a tyrosine compound and/or anti-inflammatory compoundsare then added if desired.

[0047] After the other ingredients have been added to the solution, thepH is adjusted by adding an appropriate amount of a base such as sodiumhydroxide or sodium carbonate to produce a pH of about 3.8 to about 4.0. The resulting solution can be employed as a topical composition inthis form (i.e., a “serum”) or may be used to produce any of a varietyof conventional formulations well known to those skilled in the art,e.g., as a cream, lotion or gel.

[0048] The present topical composition may be in the form of an aqueoussolution (i.e., “serum”) or blended into a tissue compatible vehicle,such as hydrophilic lotion-, ointment-, cream- or gel-based vehicle.Such vehicles are well known in the art and commercially available forformulation of active ingredients into a suitable form for topicalapplication. Exemplary of such vehicles are the commercially availableDermabase and Unibase formulations.

[0049] The present compositions may include one or more of a variety ofoptional ingredients, such as coloring agents, opacifying agents and thelike. The compositions may include, in addition to the componentsdescribed hereinabove, other active ingredients, such as antibiotics,analgesics, anti-allergenics and the like. The formulation is commonlyapplied to the skin as a lotion or cream to be rubbed on body tissueover the desired area. For optimum efficacy treatment in accordance withthe presented method should be initiated as early as possible followingexposure to sunlight or another radiation source or upon the occurrenceof a rosacea outbreak, rash, dermatitis, adult acne or otherinflammatory skin response. Generally, a composition of the presentinvention may be applied to the skin once or twice daily. As notedelsewhere herein, the present composition may be used to inhibit theeffects of aging and/or photo damage on the skin, or to treat rosacea,rash, dermatitis or other inflammatory skin complaint.

[0050] Upon formulation, compositions will be administered in a mannercompatible with the formulated dosage and in such amount and frequencyas is therapeutically effective. The compositions of the presentinvention are easily administered in a variety of administration formssuitable for direct topical application on skin. Pharmaceuticallyacceptable forms of administration include, but are not limited to,lotions, ointments, foams, emollients, microsphere and otherencapsulants including time-release encapsulants, patches including,e.g., transdermal patches, shampoos, skin or hair conditioners, pomades,sprays or aerosols, water-based solutions, oil/water emulsifications,gels, sera, unguents, salves, soaps, waxes, paraffins, gums, creams,tonics, elixirs, embrocations, lenitives, liniments, medicaments, balms,balsams, palliatives and any combination of administration formssuitable for topical application on skin.

[0051] For topical administration in an aqueous solution, for example,the ascorbic acid/ascorbate mixture, tyrosine compound and zinc saltcontaining compositions of the present invention, including thoseembodiments containing glucosamine or other anti-inflammatoryaminosugar, may be used directly on the skin without any toxic effectsto the animal or patient. Alternatively, the ascorbic acid/ascorbatemixture, tyrosine compound and zinc salt containing compositionsidentified herein, including those containing glucosamine or otheranti-inflammatory aminosugar, may be dissolved or resuspended in asuitable buffer prior to mixing, if necessary. Liquid diluents may firstbe rendered isotonic with sufficient saline or glucose solutions.

[0052] The present aqueous solutions are especially suitable for topicaladministration. As discussed above, however, other ascorbic acid-basedformulations, including those containing glucosamine or otheranti-inflammatory aminosugar, may also be used quite effectively. Somevariation in dosage will necessarily occur depending on the condition ofthe subject being treated. The person responsible for administrationwill, in any event, determine the appropriate dose for the individualsubject. Moreover, for human administration, preparations should meetsterility, pyrogenicity, general safety and purity standards as requiredby FDA Office of Biologics standards.

[0053] The topical compositions of the present invention may be includedin lotions and creams, which may be a dermatologically acceptableemollient. Such compositions may contain from about 2% to about 50% ofthe emollient. An “emollient” as defined herein is a material useful forthe prevention or relief of dryness, as well as for the protection ofthe skin. Many suitable emollients are known and may be used with thepresent invention, see e.g., Sagarin, Cosmetics, Science and Technology,2nd Edition, Vol. 1, pp. 32-43 (1972), relevant portions incorporatedherein by reference. A material suitable as an emollient is, e.g.,glycerin. Glycerin may be used in an amount of from or about 0.001 to orabout 20%, from or about 0.01 to or about 10, or even from about 0.1 toor about 5%, e.g., 3%.

[0054] Lotions and creams may also include a solution carrier system andone or more emollients. Lotions typically include from about 1% to about20%, from about 5% to about 10%, of emollient; from about 50% to about90%, from about 60% to about 80%, water; and other ingredients in theabove described amounts. A cream includes typically from about 5% toabout 50%, from about 10% to about 20%, of emollient; from about 45% toabout 85%, from about 50% to about 75%, water; and other ingredients inthe above described amounts.

[0055] Ointments of the present invention may include a simple carrierbase of animal or vegetable oils or semi-solid hydrocarbons(oleaginous); absorption ointment bases which absorb water to formemulsions; or water soluble carriers, e.g., a water soluble solutioncarrier. Ointments may further include a thickening agent, such asdescribed in Sagarin, Cosmetics, Science and Technology, 2nd Edition,Vol. 1, pp. 72-73 (1972), incorporated herein by reference, and/or anemollient. For example, an ointment may include from about 2% to about10% of an emollient; from about 0.1% to about 2% of a thickening agent;and other ingredients in the above described amounts.

[0056] Compositions of this invention useful for cleansing (“cleansers”)may be formulated with a suitable carrier, e.g., as described above, andcontain, in addition to the ingredients in the amounts described above,from about 1% to about 90%, or from about 5% to about 10%, of adermatologically acceptable surfactant. Surfactants may be selected fromanionic, nonionic, zwitterionic, amphoteric and ampholytic surfactants,as well as mixtures of these surfactants. Such surfactants are wellknown to those skilled in the detergency art. Examples of surfactantsinclude isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyltaurate, and sodium lauryl sulfate, see e.g., U.S. Pat. No. 4,800,197,to Kowcz et al., issued Jan. 24, 1989, relevant portions incorporatedherein by reference, for exemplary surfactants. Examples of a broadvariety of additional surfactants are described in McCutcheon'sDetergents and Emulsifiers, North American Edition (1986), published byAllured Publishing Corporation, relevant portions incorporated herein byreference. The cleansing compositions may contain, at theirart-established levels, other materials that are used conventionally incleansing compositions.

[0057] The physical form of the cleansing, cream, lotion and othercompositions is not critical. The compositions may be, for example,formulated as toilet bars, liquids, shampoos, bath gels, hairconditioners, hair tonics, pastes, or mousses. Toilet bars may beprovided as a cleansing agent most commonly used to wash the skin, e.g.,the face or scalp. Cleansing compositions that rinse-off, such asshampoos, may require a delivery system adequate to deposit sufficientlevels of actives on the skin and scalp. One such delivery systeminvolves the use of insoluble complexes. For a more complete disclosureof such delivery systems, see U.S. Pat. No. 4,835,148, Barford et al.,issued May 30, 1989, relevant portions incorporated herein by reference.

[0058] The present invention may also be formulation as a foundation. Asused herein, the term “foundation” refers to a liquid, semi-liquid,semi-solid, or solid skin cosmetic that includes, but is not limited tolotions, creams, gels, pastes, cakes, and the like. Typically,foundations are used over a large area of the skin, such as over theface, to provide a particular look. Foundations are used typically toprovide an adherent base for color cosmetics such as rouge, blusher,powder and the like, and tend to hide skin imperfections and impart asmooth, even appearance to the skin.

[0059] Foundations will find particular usefulness in the presentinvention when used to not only reduce the level of inflammationassociated with skin conditions such as rosacea, adult acne and thelike, but also provide a make-up that will cover the treatment areasuntil the skin returns to its pre-inflammatory state. Foundations mayinclude a dermatologically acceptable carrier for the formulations ofthe present invention, e.g., oils, colorants, pigments, emollients,fragrances, waxes, stabilizers and the like.

[0060] The compositions of the present invention may further include anon-toxic zinc salt. Zinc salts for use with the present invention mayinclude zinc acetate, zinc acetate hydrates, zinc aluminum oxidecomplexes, zinc bromate, zinc bromide, zinc carbonates, zinc chloratehydrates, zinc chloride, zinc diamine dichloride, zinc citrate, zincchromate, zinc dichromate, zinc diphosphate, zinc hexacyanofluorideferrate (II), zinc fluoride, zinc fluoride hydrates, zinc formate, zincformate hydrates, zinc hydroxide, zinc iodate, zinc iodate, zinc iodide,zinc iron oxide complexes, zinc nitrate hydrates, zinc nitride, zincoxalate hydrates, zinc oxides, zinc perchlorate, zinc permanganatehydrates, zinc peroxide, zinc p-phenolsulfonate hydrates, zincphosphate, zinc phosphate hydrates, zinc phosphide, zinc propionate,zinc selenate hydrates, zinc selenide, zinc silicates, zinc siliconoxide water complexes, zinc hexafluorosilicate hydrates, zinc stearate,zinc sulfate, zinc sulfate hydrates, zinc sulfide, zinc sulfite, zinctelluride, zinc thiocyanate, zinc (II) salts of N-acetyl L-cysteine, andmixtures thereof. Zinc salts may also include zinc citrate, zinc oxide,zinc chloride, zinc acetate, zinc stearate, zinc sulfate, and mixturesthereof, with Zinc citrate being particularly useful.

[0061] The compositions of the present invention may also include one ormore humectants or moisturizers. A variety of these materials may beused at amount ranging from about 0.1% to about 20%, from about 0.5% toabout 15%, and from about 1% to about 10%. Examples of humectantsinclude materials selected from the group consisting of guanidine;glycolic acid and glycolate salts (e.g., ammonium and quaternary alkylammonium); lactic acid and lactate salts (e.g., ammonium and quaternaryalkyl ammonium); aloe vera in any of its variety of forms (e.g., aloevera gel); polyhydroxy alcohols such as sorbitol, glycerol, hexanetriol,propylene glycol, butylene glycol, hexylene glycol and the like;polyethylene glycols; sugars and starches; sugar and starch derivatives(e.g., alkoxylated glucose); hyaluronic acid; lactamidemonoethanolamine; acetamide monoethanolamine; and mixtures thereof.

[0062] A particular humectant for use herein is glycerol. Othermaterials that may be used in conjunction with the present inventioninclude: almond meal, alumina, aluminum oxide, aluminum silicate,apricot seed powder, attapulgite, barley flour, bismuth oxychloride,boron nitride, calcium carbonate, calcium phosphate, calciumpyrophosphate, calcium sulfate, cellulose, chalk, chitin, clay, corn cobmeal, corn cob powder, corn flour, corn meal, corn starch, diatomaceousearth, dicalcium phosphate, dicalcium phosphate dihydrate, fullersearth, hydrated silica, hydroxyapatite, iron oxide, jojoba seed powder,kaolin, magnesium trisilicate, mica, microcrystalline cellulose,montmorillonite, oat bran, oat flour, oatmeal, peach pit powder, pecanshell powder, polybutylene, polyethylene, polyisobutylene,polymethylstyrene, polypropylene, polystyrene, polyurethane, nylon,teflon (i.e. polytetrafluoroethylene), polyhalogenated olefins, pumicerice bran, rye flour, cericite, silica, silk, sodium bicarbonate, sodiumsilicoaluminate, soy flour synthetic hectorite, talc, tin oxide,titanium disoide, tricalcium phosphate, walnut shell powder, wheat bran,wheat flour, wheat starch, zirconium silicate, and mixtures thereof.Also useful are mixed polymers (e.g., copolymers terpolymers, etc.),such as polyethlene/polypropylene copolymer,polyethylene/propylene/isobutylene copolymer, polyethlene/styrenecopolymer, and the like. Typically, the polymeric and mixed polymericparticles are treated via an oxidation process to destroy impurities andthe like. The polymeric and mixed polymeric particles may also becrosslinked with a variety of common crosslinking agents. Examples ofcommon cross-linking agents include: butadiene, di-vinyl benzene,methylenebisacrylamide, allyl ethers of sucrose, allyl ethers ofpentaerythritol, and mixtures thereof. Other examples of usefulparticles include waxes and resins, such as: paraffins, carnuba wax,ozekerite wax, candellila wax, urea-formaldehyde resins and the like.When waxes and resins are used it is important that these materials aresolids at ambient and skin temperatures.

[0063] The present invention also includes methods for delivering aneffective amount of the composition of the present invention whenapplied to the skin. These compositions are useful for conditioning andtreating e.g., inflamed, dry, aging and damaged skin.

[0064] The compositions of the present invention are useful for personaltreatment and cleansing, especially of exposed areas of the skin such asface and neck. Typically, a suitable or effective amount of thecomposition is applied to the area to be treated. Alternatively, asuitable amount of the composition may be applied via intermediateapplication to a washcloth, sponge, pad, cotton ball or otherapplication device. If necessary, the area to be treated may be cleanedor pre-moistened with water and/or a thin layer of an ointment, cream,oil and the like. It has been found that the compositions of the presentinvention may cause a mild irritation in patients with sensitive skinswhen applied directly. In those cases where skin irritation is aproblem, the subject may apply a cream or other lotion to the areabefore using the composition of the present invention to reduce thelevel of skin irritation. Alternatively, the composition may be used orprovided along with and wiped-off from the skin using a pad, cottonball, tissue or other like device. The cleansing process is typically atwo-step process involving application of the composition followedeither by rinsing of the produce with water or wiping without the use ofwater. An effective amount of composition to be used will depend uponthe needs of the individual.

[0065] While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention. Various modifications and combinations of the illustrativeembodiments, as well as other embodiments of the invention, will beapparent to persons skilled in the art upon reference to thedescription.

What is claimed is:
 1. A composition comprising: at least about 10% ofthe ascorbic acid, wherein the ascorbic acid comprises pretreatedascorbic acid; an aminosugar; and water.
 2. The composition of claim 1,wherein the composition has a pH of more than 3.5.
 3. The composition ofclaim 1, further comprising a non-toxic zinc salt.
 4. The composition ofclaim 1, further comprising a tyrosine compound.
 5. The composition ofclaim 1, wherein the aminosugar comprises glucosamine.
 6. Thecomposition of claim 1, wherein the ascorbic acid comprisesmonodehydroascorbic acid.
 7. The composition of claim 1, furthercomprising an administration form suitable for topical application. 8.The composition of claim 1, wherein the composition is topicallytherapeutic against inflammatory skin conditions.
 9. The composition ofclaim 1, wherein the composition comprises a serum, a lotion, anointment, a cream, a gel, a foam, an emollient, microspheres and otherencapsulants including time-release encapsulants, a patch, a transdermalpatch, a shampoo, a skin or hair conditioner, a pomade, a spray oraerosol, a water-based solution, an oil/water emulsification, anunguent, a salve, a soap, a wax, a paraffin, a gum, a tonic, an elixir,an embrocation, a lenitive, a liniment, a medicament, a balm, a balsam,a palliative or any combination of administration forms suitable fortopical application on skin.
 10. The composition of claim 5, whereinglucosamine is present in the amount of approximately 20% (w/v).
 11. Thecomposition of claim 1, wherein the composition further comprises one ormore ingredients selected from the group consisting of (a) one or morenon-toxic zinc salts, (b) one or more tyrosine compounds, (c) one ormore antibacterial agents, (d) one or more dyes, (e) one or morefragrances, (f) one or more surfactants, (g) one or more thickeners, (h)one or more antioxidants, (i) one or more pharmaceutically acceptablecarriers, (j) one or more tissue compatible vehicles, one or morehumectants or moisturizers, (k) one or more polymers, (l) one or morepolymers, (m) one or more cross-linking agents, (n) one or more waxes orresins, and (o) any combination of (a)-(o).
 12. The composition of claim8, wherein the inflammatory skin condition comprises rosacea, acne, aninflammatory allergic skin reaction, hypersensitivity, rash ordermatitis.
 13. The composition of claim 1, wherein the composition isadapted for use as foundation.
 14. The composition of claim 1, whereinthe composition is adapted for use as cleanser.
 15. The composition ofclaim 1, wherein the water is distilled or deionized water.
 16. Thecomposition of claim 1, wherein the composition further comprises one ormore ingredients selected from the group consisting of: almond meal,alumina, aluminum oxide, aluminum silicate, apricot seed powder,attapulgite, barley flour, bismuth oxychloride, boron nitride, calciumcarbonate, calcium phosphate, calcium pyrophosphate, calcium sulfate,cellulose, chalk, chitin, clay, corn cob meal, corn cob powder, cornflour, corn meal, corn starch, diatomaceous earth, dicalcium phosphate,dicalcium phosphate dihydrate, fullers earth, hydrated silica,hydroxyapatite, iron oxide, jojoba seed powder, kaolin, magnesiumtrisilicate, mica, microcrystalline cellulose, montmorillonite, oatbran, oat flour, oatmeal, peach pit powder, pecan shell powder,polybutylene, polyethylene, polyisobutylene, polymethylstyrene,polypropylene, polystyrene, polyurethane, nylon, teflon (i.e.polytetrafluoroethylene), polyhalogenated olefins, pumice rice bran, ryeflour, cericite, silica, silk, sodium bicarbonate, sodiumsilicoaluminate, soy flour synthetic hectorite, talc, tin oxide,titanium disoide, tricalcium phosphate, walnut shell powder, wheat bran,wheat flour, wheat starch, zirconium silicate, or mixtures thereof. 17.A composition for treating an inflammatory skin ailment, the compositioncomprising: at least about 5.0% (w/v) ascorbic acid, wherein at leastabout 10% of the ascorbic acid is pretreated ascorbic acid; at leastabout 10% (w/v) of glucosamine; a non-toxic zinc salt; a tyrosinecompound; and water, wherein the composition has a pH of more than 3.5.18. A method of treating rosacea or other inflammatory skin affliction,the method comprising topically applying to the afflicted skin acomposition comprising at least 5.0% (w/v) ascorbic acid, wherein atleast about 10% (w/v) of the ascorbic acid is pretreated ascorbic acid;at least 10% (w/v) glucosamine or other anti-inflammatory aminosugar;and water.
 19. The method of claim 13, wherein the composition furthercomprises one or more ingredients selected from the group consisting ofa (a) one or more non-toxic zinc salts, (b) one or more tyrosinecompounds, (c) one or more antibacterial agents, (d) one or more dyes,(e) one or more fragrances, (f) one or more surfactants, (g) one or morethickeners, (h) one or more antioxidants and (i) any combination of(a)-(h).
 20. The method of claim 13, wherein the composition iscomprises a serum, a lotion, an ointment, a cream, a gel, a foam, anemollient, microspheres and other encapsulants including time-releaseencapsulants, a patch, a transdermal patch, a shampoo, a skin or hairconditioner, a pomade, a spray or aerosol, a water-based solution, anoil/water emulsification, an unguent, a salve, a soap, a wax, aparaffin, a gum, a tonic, an elixir, an embrocation, a lenitive, aliniment, a medicament, a balm, a balsam, a palliative or anycombination of administration forms suitable for topical application onskin.